Abstract:

The disclosure relates to biocompatible components useful for forming
compositions for use as medical/surgical synthetic adhesives and
sealants. Biocompatible components of the present disclosure may include
a polymeric polyol core, which may be treated with a nitroaryl compound
to form a nitro ester. The resulting nitro ester groups may be reduced to
form amino groups which, in turn, may be treated to form isocyanate
groups. The resulting isocyanate may then be reacted with a second
component to form adhesive and/or sealant compositions.

Claims:

1. A biocompatible component comprising: ##STR00024## wherein R is
selected from the group consisting of alkyl groups, cycloalkyl groups,
alkenyl groups, alkynyl groups, alkylene groups, cycloalkylene groups,
alkenylene groups, alkynylene groups, aromatic groups, heteroaromatic
groups, heterocyclic groups, and combinations thereof;n can be from 1 to
5;R1 can be the same or different at each location and is selected
from the group consisting of CH2, alkyl, OCH2, SCH2,
NHCH2, O-alkyl, S-alkyl, NH-alkyl, O-aryl, NH-aryl, and combinations
thereof; andPAO is a polyalkylene oxide having a molecular weight of from
about 200 to about 4000.

2. The biocompatible component of claim 1, wherein R is selected from the
group consisting of methylene, ethylene, propylene, butylene,
cyclohexylene, phenylene, pyridylene, and combinations thereof.

4. A composition comprising the biocompatible component of claim 1 in
combination with a second component.

5. The composition of claim 4, wherein the second component comprises a
polyol.

6. The composition of claim 5, wherein the polyol is selected from the
group consisting of glycerol, trimethylol propane, hexane-1,2,6-triol,
polycaprolactone triol, polyalkylene oxides, and combinations thereof.

7. The composition of claim 4, wherein the biocompatible component of
claim 1 is present in an amount from about 50 to about 90 percent by
weight of the composition, and the second component is present in an
amount from about 10 to about 50 percent by weight of the composition.

8. A method for closing a wound comprising:applying the composition of
claim 4 to said wound; andallowing the composition to set thereby closing
said wound.

9. A method for sealing a leak in animal tissue comprising:applying the
composition of claim 4 to said leak; andallowing the composition to set
thereby sealing said leak.

10. A method for adhering a medical device to a surface of animal tissue
comprising:applying the composition of claim 4 to said device, said
surface or both;bringing the device, composition and surface into contact
with each other; andallowing the composition to set thereby adhering the
device and surface to each other.

11. A method comprising:contacting a polyol with a nitroaryl carboxylic
derivative to form a compound selected from the group consisting of
nitroaryl esters and nitroaryl ethers;contacting the nitroaryl esters and
nitroaryl ethers with a reducing agent selected from the group consisting
of palladium with hydrogen, palladium with ammonium formate, platinum
oxide with hydrogen, nickel with hydrogen, tin(II) chloride, iron with
acetic acid, aluminum with ammonium chloride, borane, sodium dithionite,
hydrazine, and combinations thereof, to form a second compound selected
from the group consisting of amino esters and amino ethers;converting the
amino ester or the amino ether to a corresponding isocyanate ester or
isocyanate ether by contact with a reactant selected from the group
consisting of phosgene, diphosgene, triphosgene, 4-nitrophenyl
chloroformate, and combinations thereof, optionally in the presence of a
base, optionally in the presence of an aprotic solvent; andrecovering the
isocyanate ester or isocyanate ether.

13. The method of claim 11, wherein the nitroaryl carboxylic derivative
comprises an aromatic ring with a nitrogen attached thereto, with at
least one carboxylic acid group that is not directly linked to the
aromatic ring.

15. The method of claim 11, wherein the nitroaryl carboxylic derivative is
formed by a reaction with a component selected from the group consisting
of oxalyl chloride, thionyl chloride, dicyclohexyl carbodiimide,
diisopropyl carbodiimide, carbonyl diimidazole, 1-hydroxybenzotriazole,
1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride, and
combinations thereof.

16. The method of claim 11, wherein the polyol and the nitroaryl
carboxylic derivative are combined at a temperature of from about
0.degree. C. to about 80.degree. C., for a period of time of from about 3
hours to about 24 hours.

17. The method of claim 11, wherein the polyol and the nitroaryl
carboxylic derivative are combined in solution, utilizing a solvent
selected from the group consisting of ethyl acetate, tetrahydrofuran,
dioxane, propyl acetate, and combinations thereof.

18. The method of claim 11, wherein converting the amino ester or the
amino ether to the corresponding isocyanate ester or isocyanate ether
occurs in the presence of a base selected from the group consisting of
triethylamine, pyridine, diisopropylethylamine, sodium carbonate, and
combinations thereof, and also occurs in the presence of an aprotic
solvent selected from the group consisting of tetrahydrofuran, dioxane,
ethyl acetate, propyl acetate, and combinations thereof.

Description:

[0001]This application claims priority to U.S. Provisional Patent
Application Ser. No. 61/153,714 filed on Feb. 19, 2009, the disclosure of
which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

[0002]The present disclosure relates to adhesives and sealants formed from
synthetic components for medical and surgical use with animal tissues in
vivo.

BACKGROUND OF RELATED ART

[0003]In recent years there has developed an increased interest in
replacing or augmenting sutures with adhesive bonds. The reasons for this
increased interest include: (1) the potential speed with which repair
might be accomplished; (2) the ability of a bonding substance to effect
complete closure, thus preventing seepage of fluids; and (3) the
possibility of forming a bond without excessive deformation of tissue or
additional injury to tissue.

[0004]Studies in this area, however, have revealed that in order for
surgical adhesives to be accepted by surgeons, they should possess
various properties. For example, they should exhibit high initial tack
and an ability to bond rapidly to living tissue; the strength of the bond
should be sufficiently high to cause tissue failure before bond failure;
the adhesive should form a bridge, typically a permeable flexible bridge;
and the adhesive bridge and/or its metabolic products should not cause
local histotoxic or carcinogenic effects.

[0005]Several materials useful as tissue adhesives or tissue sealants are
currently available. One type of adhesive that is currently available is
a cyanoacrylate adhesive. However, there is the possibility that a
cyanoacrylate adhesive can degrade to generate undesirable by-products
such as formaldehyde. Another disadvantage with cyanoacrylate adhesives
is that they can have a high elastic modulus which can limit their
usefulness.

[0006]Another type of tissue sealant that is currently available utilizes
components derived from bovine and/or human sources. For example, fibrin
sealants are available. However, as with any natural material,
variability in the material is frequently observed and, because the
sealant is derived from natural proteins, there may be viral transmission
concerns.

[0007]It would be desirable to provide a surgical adhesive or sealant that
is fully synthetic and therefore highly consistent in its properties
without the concern of viral transmission. Such a composition should be
flexible and biocompatible and should be suitable for use as an adhesive
or sealant.

SUMMARY

[0008]Biocompatible compositions are provided which may be utilized, in
embodiments, as tissue adhesives and/or tissue sealants. In embodiments,
a biocompatible composition of the present disclosure may include a
component of the following formula:

##STR00001##

[0009]wherein R can be alkyl groups, cycloalkyl groups, alkenyl groups,
alkynyl groups, alkylene groups, cycloalkylene groups, alkenylene groups,
alkynylene groups, aromatic groups, heteroaromatic groups, heterocyclic
groups, and combinations thereof, and n is a whole number from about 1 to
about 5, in embodiments from about 2 to about 3;

[0010]R1 can be the same or different at each location and can be
CH2, alkyl, OCH2, SCH2, NHCH2, O-alkyl, S-alkyl,
NH-alkyl, O-aryl, NH-aryl, and combinations thereof; and

[0011]PAO is a polyalkylene oxide having a molecular weight of from about
200 to about 4000.

[0012]Processes for making these biocompatible compositions are also
provided. In embodiments, a process of the present disclosure may include
contacting a polyol with a nitroaryl carboxylic derivative to form a
compound such as nitroaryl esters and/or nitroaryl ethers; contacting the
nitroaryl esters and/or nitroaryl ethers with a reducing agent such as
palladium with hydrogen, palladium with ammonium formate, platinum oxide
with hydrogen, nickel with hydrogen, tin(II) chloride, iron with acetic
acid, aluminum with ammonium chloride, borane, sodium dithionite,
hydrazine, and combinations thereof, to form a second compound including
amino esters and amino ethers; converting the amino ester or the amino
ether to a corresponding isocyanate ester or isocyanate ether by contact
with a reactant such as phosgene, diphosgene, triphosgene, 4-nitrophenyl
chloroformate, and combinations thereof, optionally in the presence of a
base, optionally in the presence of an aprotic solvent; and recovering
the isocyanate ester or isocyanate ether.

[0013]Methods for using the compositions of the present disclosure as
tissue adhesives and/or tissue sealants are also provided. In
embodiments, such methods may include closing wounds, sealing leaks in
animal tissue, adhering medical devices to tissue, combinations thereof,
and the like.

DETAILED DESCRIPTION

[0014]The present disclosure relates to biocompatible compositions for use
as tissue adhesives or sealants, which are non-immunogenic and
biodegradable. The biocompatible compositions can be employed to
approximate tissue edges, adhere medical devices (e.g. implants) to
tissue, seal air/fluid leaks in tissues, and for tissue augmentation such
as sealing or filling voids or defects in tissue. Thus, as used herein,
an "adhesive" is understood to include a composition which adheres one
thing to another, such as tissue edges to each other, or a device, such
as an implant, to tissue; and a "sealant" is understood to include a
composition which is applied to tissue and utilized to seal air/fluid
leaks in tissue or seal or fill small voids or defects in tissue.
However, an adhesive composition herein may be used as a sealant, and a
sealant composition may be used as an adhesive.

[0015]The biocompatible compositions can be applied to living tissue
and/or flesh of animals, including humans. While certain distinctions may
be drawn between the usage of the terms "flesh" and "tissue" within the
scientific community, the terms are used interchangeably herein as
referring to a general substrate upon which those skilled in the art
would understand the present composition to be utilized within the
medical field for the treatment of patients. As used herein, "tissue" may
include, but is not limited to, skin, bone, neuron, axon, cartilage,
blood vessel, cornea, muscle, fascia, brain, prostate, breast,
endometrium, lung, pancreas, small intestine, blood, liver, testes,
ovaries, cervix, colon, stomach, esophagus, spleen, lymph node, bone
marrow, kidney, peripheral blood, embryonic tissue, and/or ascite tissue.

[0016]In accordance with the present disclosure, a biocompatible component
is provided which includes a polymeric core. Suitable cores which may be
utilized include, but are not limited to, polymeric polyols, including
polymeric diols such as polyether diols, polyester diols,
polyester-urethane diols, combinations thereof, and the like. Other
polymeric polyols which may be utilized to form a polymeric core in
accordance with the present disclosure include, but are not limited to,
block copolymers including branched chain ethoxylated alcohols;
alkoxylated alcohols such as NEODOL® which is sold commercially by
Shell Chemical Company; polyvinyl alcohols; polyhydric alcohols;
carboxylic acid esters of polyhydric alcohols; polyglycols; polylactone
polyols; combinations thereof, and the like.

[0018]In other embodiments, suitable polyols for use as the polymeric
polyol include polyester-based polyols such as polycaprolactone-based
polyols including diols, polylactide-based polyols including diols,
polyglycolide-based polyols including diols, combinations thereof, and
the like.

[0019]In other embodiments, the polymeric core may include more than one
polyalkylene oxide reacted with a dicarboxylic acid, the dicarboxylic
acid including a methylene or other alkylene group, a cycloalkylene
group, an aromatic group, a heteroaromatic group, or combinations
thereof. Examples of such groups include, but are not limited to,
methylene, ethylene, propylene, butylene, cyclohexylene, phenylene,
pyridylene, combinations thereof, and the like.

[0020]In some embodiments, the polyol, including the diols described
above, may be functionalized by reacting them with additional components
including, but not limited to, acids such as sebacic acid, azelaic acid,
suberic acid, pimelic acid, adipic acid, glutaric acid, succinic acid,
malonic acid, oxalic acid, terephthalic acid, cyclohexyldicarboxylic
acid, pyridine dicarboxylic acid, combinations thereof, and the like,
thereby forming esters. In embodiments, PEG esters may be formed and
utilized as the polymeric polyol component. In such a case, the polyol
may be present in an amount of from about 66% to about 97% by weight of
the ester, in embodiments from about 70% to about 90% by weight of the
ester, with the acid present in an amount of from about 3% to about 34%
by weight of the ester, in embodiments from about 10% to about 30% by
weight of the ester.

[0021]In other embodiments, a branched polyol may be utilized to form the
core, including a branched polyether diol or a branched polyester diol.

[0022]In embodiments, the polymeric polyol can have a molecular weight of
from about 400 grams/mol to about 5000 grams/mol, in embodiments from
about 850 grams/mol to about 2000 grams/mol.

[0023]In embodiments, the polyol can then be converted to an isocyanate
prepolymer. In accordance with the present disclosure, the above polyol,
such as a polyester diol or polyether diol, may be converted into an
isocyanate prepolymer, in embodiments a diisocyanate prepolymer, by first
converting them to nitroaryl esters or ethers. For example, a diol as
described above may be reacted with a nitroaryl carboxylic acid
derivative. As used herein, in embodiments, a nitroaryl carboxylic acid
derivative includes an aromatic ring with at least one nitro group
attached thereto, with at least one carboxylic acid group or derivative
that is not directly linked to the aromatic ring. Suitable nitroaryl
carboxylic acid derivatives include for example, o-nitrophenylacetic
acid, m-nitrophenylacetic acid, p-nitrophenylacetic acid,
o-nitrophenoxyacetic acid, m-nitrophenoxyacetic acid,
p-nitrophenoxyacetic acid, 4-nitrohippuric acid, o-nitrocinnamic acid,
m-nitrocinnamic acid, p-nitrocinnamic acid, combinations thereof, and the
like.

[0024]In embodiments, prior to reacting the polyol with the nitroaryl
carboxylic acid, the carboxylic acid group can be activated by treatment
with oxalyl chloride, thionyl chloride, dicyclohexyl carbodiimide,
diisopropyl carbodiimide, carbonyl diimidazole, 1-hydroxybenzotriazole,
1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCl),
combinations thereof and the like. The amount of reagent added to the
nitroaryl carboxylic acid derivative may be from about 1 to about 2.5
molar equivalents, in embodiments from about 1.2 to 1.6 molar equivalent.

[0025]The formation of the acid chloride may occur at temperatures of from
about 0° C. to about 60° C., in embodiments from about
10° C. to about 30° C., for a period of time of from about
1 hour to about 6 hours, in embodiments from 1.5 hours to about 3 hours.
The formation of the acid chloride may optionally occur with the addition
of a catalyst, for example dimethyl formamide in the cases where oxalyl
chloride or thionyl chloride are used as reagents.

[0026]The nitroaryl carboxylic acid derivative may be combined with the
polyol to produce a nitroaryl ester by any means within the purview of
those skilled in the art, including mixing, blending, combinations
thereof and the like. The nitroaryl carboxylic acid derivative and the
polyol may be combined at temperatures of from about 0° C. to
about 80° C., in embodiments from about 25° C. to about
60° C., for a period of time from about 3 hours to 24 hours, in
embodiments from about 5 hours to 16 hours. In embodiments, the reaction
may occur in solution, utilizing a suitable solvent such as, for example,
ethyl acetate, tetrahydrofuran (THF), dioxane, toluene, combinations
thereof, and the like.

[0027]The nitroaryl ester thus produced may be recovered from solution
utilizing any means within the purview of those skilled in the art,
including, for example, washing and filtration, precipitation,
crystallization, chromatography, combinations thereof, and the like.

[0028]The amounts of the nitroaryl carboxylic acid derivative and the
polyol may be varied depending upon the desired end-use, with the
nitroaryl carboxylic acid derivative present in an amount of from about
8% by weight to about 42% by weight of the nitroaryl ester, in
embodiments from about 15% by weight to about 24% by weight of the
nitroaryl ester, and the polyol present in an amount from about 58% by
weight to about 92% by weight of the nitroaryl ester, in embodiments from
76% by weight to about 85% by weight of the nitroaryl ester.

[0029]In embodiments, the resulting nitroaryl ester or ether may then be
converted to an aminoester or aminoether by a reduction reaction.
Examples of suitable reducing agents for this reduction reaction include,
but are not limited to, palladium with hydrogen, palladium with ammonium
formate, platinum oxide with hydrogen, nickel with hydrogen, tin(II)
chloride, iron with acetic acid, aluminum with ammonium chloride, borane,
sodium dithionite, hydrazine, combinations thereof, and the like. The
amount of reducing agent utilized to carry out the reduction reaction to
form an aminoester may be from about 2 molar equivalents to about 20
molar equivalents, in embodiments about 6 molar equivalents to about 15
molar equivalents.

[0030]The reduction reaction may occur by combining the components
utilizing any means within the purview of those skilled in the art,
including mixing, blending, combinations thereof, and the like. The
reactants utilized in the reduction reaction may optionally be heated to
a temperature of from about 30° C. to about 120° C., in
embodiments from about 50° C. to about 80° C. In
embodiments, the reaction may occur in solution, utilizing a suitable
solvent such as, for example, ethyl acetate, tetrahydrofuran, dioxane,
propyl acetate, combinations thereof, and the like.

[0031]The aminoester thus produced may be recovered from solution
utilizing any means within the purview of those skilled in the art
including, for example, washing and filtration, precipitation,
crystallization, chromatography, combinations thereof, and the like.

[0032]The resulting aminoester or aminoether may then be converted to an
isocyanate ester or ether by reacting with a suitable reactant including,
for example, phosgene, diphosgene, triphosgene, 4-nitrophenyl
chloroformate, combinations thereof, and the like. The components
utilized to form the isocyanate may be combined using any means within
the purview of those skilled in the art including, for example, mixing,
blending, combinations thereof, and the like. The components utilized to
form the isocyanate may be optionally heated to a temperature of from
about 30° C. to about 120° C., in embodiments from about
45° C. to about 80° C. The formation of the isocyanate may
optionally occur in the presence of a base, such as triethylamine,
pyridine, diisopropylethylamine, sodium carbonate, combinations thereof,
and the like, and optionally in an aprotic solvent such as
tetrahydrofuran (THF), dioxane, ethyl acetate, propyl acetate,
combinations thereof, and the like.

[0033]The amount of reactants such as phosgene, diphosgene, triphosgene,
4-nitrophenylchloroformate and the like utilized to form the isocyanate
may be from about 1 molar equivalent to about 3 molar equivalents, in
embodiments from about 1.2 molar equivalents to about 1.75 molar
equivalents, relative to the amine.

[0034]The resulting isocyanate ester or isocyanate ether, sometimes
referred to, in embodiments, as a biocompatible isocyanate, may thus, in
embodiments, be of the following formula

##STR00002##

[0035]where R can be alkyl groups, cycloalkyl groups, alkenyl groups,
alkynyl groups, alkylene groups, cycloalkylene groups, alkenylene groups,
alkynylene groups, aromatic groups, heteroaromatic groups, heterocyclic
groups, and combinations thereof, and n is a whole number from about 1 to
about 5, in embodiments from about 2 to about 3;

[0036]R1 can be CH2, alkyl, OCH2, SCH2, NHCH2,
O-alkyl, S-alkyl, NH-alkyl, O-aryl, and/or NH-aryl, and R1 can be
the same or different at each location; and

[0037]PAO is polyalkylene oxide as described above, in embodiments
polyethylene glycol, having a molecular weight of from about 200 to about
4000, in embodiments from about 600 to about 2000.

[0039]The isocyanate thus produced may then be reacted with a second
component to form an adhesive or sealant composition in accordance with
the present disclosure. As would be readily apparent to one skilled in
the art, the desired properties of the compositions of the present
disclosure can be adjusted by the selection of the specific components
utilized to prepare the resulting adhesive or sealant compositions.

[0040]Suitable second components that may be reacted with the
biocompatible isocyanate described above (i.e., the isocyanate esters or
isocyanate ethers) include those polyols described above for use in
forming the polymeric core. In embodiments, the second component may
include another alcohol such as, for example, glycerol, trimethylol
propane, hexane-1,2,6-triol, polycaprolactone triol, polyalkylene oxides,
aminoalcohols, combinations thereof, and the like. In other embodiments,
the second component may also include polyamines, optionally in
combination with an alcohol as described above.

[0041]Other alcohols which may be utilized include any polyol obtained by
partial reaction of the polyol with, for example, polyisocyanates,
polycarboxylic acid derivatives, combinations thereof, and the like,
which permits the creation of longer polymeric molecules.

[0042]An adhesive composition and/or sealant composition of the present
disclosure may thus possess the biocompatible isocyanate component of the
present disclosure in an amount of from about 10 percent to about 100
percent by weight of the composition, in embodiments from 50 percent to
95 percent by weight of the composition, with the second component of the
adhesive composition and/or sealant composition present in an amount of
from about 0 percent to about 90 percent, in embodiments from 5 percent
to 50 percent by weight of the composition.

[0043]In some embodiments, the weight ratio of the biocompatible
isocyanate component of the present disclosure to the second component in
a composition of the present disclosure may be from 5000:1 to about 1:1,
in embodiments from 1000:1 to about 10:1.

[0044]The resulting composition of the present disclosure can be used in a
medical/surgical capacity in place of, or in combination with, sutures,
staples, clamps, combinations thereof, and the like.

[0045]Optional components may be added to the composition of the present
disclosure to adjust its viscosity according to a specific application of
use, e.g., as an adhesive or a sealant. Such optional components can
include, for example, diethylene glycol dimethyl ether ("DIGLYME"),
dimethylformamide ("DMF"), dimethyl succinate, dimethyl glutarate,
dimethyl adipate, combinations thereof, and the like. Thickening agents
which can be used to adjust the viscosity of the compositions of the
present disclosure include polycyanoacrylates, polylactic acid,
polyglycolic acid, lactic-glycolic acid copolymers, poly-3-hydroxybutyric
acid, polyorthoesters, polyanhydrides, pectin, combinations thereof, and
the like.

[0046]Where utilized, such additives can be included so that they are
present in an amount of from about 1 to about 30 percent by weight of the
composition, in embodiments from about 2 to about 15 percent by weight of
the composition.

[0048]Where utilized, such stabilizers can be included so that they are
present in an amount from about 0.01 to about 10 percent by weight of the
composition, in embodiments from about 0.1 to about 2 percent by weight
of the composition.

[0049]In some embodiments, solid supported catalysts may be used during
synthesis to improve stability of the resulting composition of the
present disclosure. The presence of such catalysts may increase
reactivity during use. Suitable catalysts are within the purview of those
skilled in the art and can include stannous octoate, triethylamine,
diethylaminoethanol, dimethylaminopyridine (DMAP), combinations thereof,
and the like. The amount of catalyst employed can be from about 0.5 grams
to about 50 grams per kilogram of the other components of the
composition.

[0050]The compositions of the present disclosure can be used for a number
of different human and animal medical applications including, but not
limited to, wound closure (including surgical incisions and other
wounds), adhesives for medical devices (including implants), void
fillers, and embolic agents. Adhesive compositions and/or sealant
compositions may be used to bind tissue together either as a replacement
of, or as a supplement to, sutures, staples, clamps, tapes, bandages, and
the like. Use of the disclosed compositions can eliminate or
substantially reduce the number of sutures normally required during
current practices, and eliminate the subsequent need for removal of
staples and certain types of sutures. The compositions of the present
disclosure thus can be particularly useful for use with delicate tissues
where sutures, clamps or other conventional tissue closure mechanisms may
cause further tissue damage.

[0051]Application of the compositions of the present disclosure, with or
without other additives, can be done by any conventional means. These
include dipping, brushing, or other direct manipulation of the
composition on the tissue surface, by syringe, such as with a mixer
nozzle, or spraying of the composition onto the surface. In open surgery,
application by hand, forceps, or the like is contemplated. In endoscopic
surgery, the composition can be delivered through the cannula of a
trocar, and spread at the site by any device within the purview of those
skilled in the art.

[0052]In embodiments, the biocompatible isocyanate component of the
present disclosure, optionally in combination with the second component,
may be dissolved in a solvent to form a solution for application.
Suitable solvents include those that are water miscible and biologically
acceptable for medical/surgical use. In some embodiments, the solvents
can include DIGLYME (diethylene glycol dimethyl ether),
N,N-dimethylformamide ("DMF"), dimethyl sulfoxide, combinations thereof,
and the like.

[0053]In embodiments, the biocompatible isocyanate component may be in a
first solution, with the at least one second component dissolved in an
aqueous media which optionally contains at least one biodegradable
thickener. Suitable biologically acceptable thickeners include
disaccharides, polysaccharides, alginates, hyaluronic acid, pectins,
dextrans, cellulosics such as carboxymethyl cellulose, methyl cellulose,
combinations thereof, and the like.

[0054]The biocompatible isocyanate component may be present in the first
solution in an amount from about 10% to about 100% by weight of the first
solution, in embodiments from about 50% to about 90% by weight of the
first solution. The amount of second component in the aqueous media,
sometimes referred to herein as a second solution, may be from about
0.01% to about 10% by weight of the second solution, in embodiments from
about 0.05% to about 5% by weight of the second solution. Where present,
a biodegradable thickener may be present in an amount from about 0% to
about 10% by weight of the second solution.

[0055]The biocompatible isocyanate component solution and the second
component solution may then be combined upon application to form a
sealant or adhesive composition of the present disclosure. For example,
the composition of the present disclosure can be dispensed from a
conventional adhesive dispenser, which may provide mixing of the
biocompatible isocyanate component and second component prior to
dispensing the adhesive or sealant. Such dispensers are disclosed, for
example, in U.S. Pat. Nos. 4,978,336, 4,361,055, 4,979,942, 4,359,049,
4,874,368, 5,368,563, and 6,527,749, the disclosures of each of which are
incorporated by reference herein.

[0056]In some embodiments, a dual-compartment applicator may be utilized
and mixing of the biocompatible isocyanate component solution and second
component solution may occur to form an adhesive upon dispensing by an
aerosol or by means of a mixing head attached to the applicator or
syringe. Other additives can be introduced into the biocompatible
isocyanate component solution, the second component solution, or both.

[0057]For example, the adhesive composition may be sprayed onto mammalian
tissue, which lowers the risk of additional mechanical stress on the
tissue. The spray application can be by any means within the purview of
those skilled in the art such that the composition can be applied as a
fine mist or aerosol. For example, the composition can be placed in a
spray bottle and delivered with a hand pump. Alternatively, the
composition can be placed in a container with a
non-chlorofluorohydrocarbon propellant (e.g., air, nitrogen, carbon
dioxide, and/or hydrocarbons) and delivered using a pressurized spray
can. In either case, the composition is passed through a fine orifice to
form a mist and delivered to the surgical location.

[0058]In other embodiments, especially where the composition of the
present disclosure is to be utilized as a void filler or to fill a defect
in an animal's body, it may be advantageous to more precisely control the
conditions and extent of cross-linking; in such a case, it may be
desirable to partially cross-link the composition prior to its use to
fill a void in animal tissue. The composition of the present disclosure
may then be applied to the void or defect and allowed to set, thereby
filling the void or defect.

[0059]To effectuate the joining of two tissue edges, the two edges may be
approximated, and the biocompatible isocyanate component may be applied
in combination with the second component. In other embodiments, the
biocompatible isocyanate component may be applied to one tissue edge, the
second component may be applied to a second tissue edge, and the two
edges then brought into contact with each other. The components crosslink
rapidly, generally taking less than one minute. The composition of the
present disclosure can thus be used as an adhesive to close a wound,
including a surgical incision. In such a case, the composition of the
present disclosure can be applied to the wound and allowed to set,
thereby closing the wound.

[0060]In another embodiment, the present disclosure is directed to a
method for using the adhesive composition of the present disclosure to
adhere a medical device to tissue, rather than secure two edges of
tissue. In some aspects, the medical device includes an implant. Other
medical devices include, but are not limited to, pacemakers, stents,
shunts and the like. In some embodiments, depending on the composition of
the medical device, a coating may be required on the medical device. In
some aspects such a coating can include the biocompatible isocyanate
component of the present disclosure in combination with the second
component. Generally, for adhering a device to the surface of animal
tissue, the composition of the present disclosure can be applied to the
device, the tissue surface, or both. In other embodiments, the
biocompatible isocyanate component of the present disclosure can be
applied to either the device or the tissue surface, with the second
component applied to the other (i.e., where the biocompatible isocyanate
component has not been applied). The device and tissue surface are then
brought into contact with each other and the composition is allowed to
set, thereby adhering the device and tissue surface to each other.

[0061]The composition of the present disclosure can also be used to
prevent post surgical adhesions. In such an application, the composition
may be applied and cured as a layer on surfaces of internal tissues in
order to prevent the formation of adhesions at a surgical site during the
healing process. In addition to the formation of adhesion barriers, in
embodiments the adhesive may be utilized to form implants such as
gaskets, buttresses or pledgets for implantation.

[0062]In another embodiment, the composition can be used to attach skin
grafts and position tissue flaps during reconstructive surgery. In still
another embodiment, the composition can be used to close tissue flaps in
periodontal surgery.

[0063]Applications for the compositions of the present disclosure also
include sealing tissues to prevent or control blood or other fluid leaks
at suture or staple lines. In embodiments, the composition can be used to
seal or adhere delicate tissue together in place of conventional tools
that may cause mechanical stress. The composition can also be used to
seal air and/or fluid leaks in tissue. Additionally, the composition can
be applied to tissue as a barrier to prevent adhesions, provide a
protective layer for delicate damaged tissue and/or provide a drug
delivery layer to a surgical site.

[0064]When used as a sealant, the composition of the present disclosure
can be used in surgery to prevent or inhibit bleeding or fluid leakage
both during and after a surgical procedure. It can also be applied to
prevent air leaks associated with pulmonary surgery. The sealant may be
applied directly to the desired area in at least an amount necessary to
seal off any defect in the tissue and seal off any fluid or air movement.

[0065]A variety of optional ingredients, including medicinal agents, may
also be added to the compositions of the present disclosure. These agents
may be added to adhesive compositions of the present disclosure, sealant
compositions of the present disclosure, or both. Additional medicinal
agents include antimicrobial agents, colorants, preservatives, or
medicinal agents such as, for example, protein and peptide preparations,
antipyretic, antiphlogistic and analgesic agents, anti-inflammatory
agents, vasodilators, antihypertensive and antiarrhythmic agents,
hypotensive agents, antitussive agents, antineoplastics, local
anesthetics, hormone preparations, antiasthmatic and antiallergic agents,
antihistaminics, anticoagulants, antispasmodics, cerebral circulation and
metabolism improvers, antidepressant and antianxiety agents, vitamin D
preparations, hypoglycemic agents, antiulcer agents, hypnotics,
antibiotics, antifungal agents, sedative agents, bronchodilator agents,
antiviral agents, dysuric agents, combinations thereof, and the like. A
phospholipid surfactant that provides antibacterial stabilizing
properties and helps disperse other materials in the compositions may
also be added to the compositions of the present disclosure.

[0066]Imaging agents such as iodine, barium sulfate, or fluorine, can also
be combined with the compositions of the present disclosure to allow
visualization of the surgical area through the use of imaging equipment,
including X-ray, MRI, and/or CAT scan.

[0067]Additionally, an enzyme may be added to the compositions of the
present disclosure to increase their rate of degradation. Suitable
enzymes include, for example, peptide hydrolases such as elastase,
cathepsin G, cathepsin E, cathepsin B, cathepsin H, cathepsin L, trypsin,
pepsin, chymotrypsin, γ-glutamyltransferase (γ-GTP), and the
like; sugar chain hydrolases such as phosphorylase, neuraminidase,
dextranase, amylase, lysozyme, oligosaccharase, and the like;
oligonucleotide hydrolases such as alkaline phosphatase,
endoribonuclease, endodeoxyribonuclease, and the like. In some
embodiments, where an enzyme is added, the enzyme may be included in a
liposome or microsphere to control the rate of its release, thereby
controlling the rate of degradation of the composition of the present
disclosure. Methods for incorporating enzymes into liposomes and/or
microspheres are within the purview of those skilled in the art.

[0068]The present compositions have a number of advantageous properties.
The resulting compositions of the present disclosure are safe and
biocompatible, possess enhanced adherence to tissue, are biodegradable,
have hemostatic potential, have low cost, and are easy to prepare and
use. The compositions also have a rapid curing time. Application of the
compositions, with or without other additives, can be done by any
conventional means. By varying the selection of the components, the
strength and elasticity of the adhesive and/or sealant composition can be
controlled, as can the gelation time.

[0069]The compositions rapidly form a compliant gel matrix, which insures
stationary positioning of tissue edges or implanted medical devices in
the desired location where the composition is utilized as an adhesive,
and a tightly adherent yet flexible seal where the composition is used as
a sealant. In either case, the rapidity of gelation lowers the overall
required surgical/application time. Where delicate or spongy tissues are
involved and/or air or fluid leaks must be sealed, spray application of a
composition may be utilized to avoid stress to the tissue and insure a
uniform coating over the area.

[0070]The compositions of the present disclosure retain the positional
integrity of the tissue to which they are applied and/or location of a
medical device. The compositions form strong cohesive bonds. They exhibit
excellent mechanical performance and strength, while retaining the
necessary pliability to adhere living tissue. This strength and
pliability allows a degree of movement of tissue without shifting the
surgical tissue edge. Additionally, the compositions are biodegradable,
allowing the degradation components to pass safely through the subject's
body.

[0071]The following Examples are being submitted to illustrate embodiments
of the present disclosure. The Examples are intended to be illustrative
only and are not intended to limit the scope of the present disclosure.
Also, parts and percentages are by weight unless otherwise indicated. As
used herein, "room temperature" refers to a temperature of from about
20° C. to about 25° C.

Example 1

[0072]A solution of p-nitrophenylacetic acid (about 12.02 grams) in THF
(about 130 ml) at room temperature was treated with oxalyl chloride
(about 12.25 grams) and two drops of N,N-dimethylformamide. The resulting
mixture was stirred at room temperature for about 1.5 hours and then
evaporated to dryness using a rotary evaporator. The resulting acid
chloride was mixed with about 50 grams of polyethylene glycol adipate
(Mw about 1658). The mixture was heated at about 70° C. for
about 16 hours. After cooling to room temperature, it was diluted with
THF (about 100 ml), treated with activated carbon (about 2 grams) and
CELITE® (about 10 grams). After stirring for about 15 minutes, the
mixture was filtered over a pad of CELITE® and washed with THF (about
50 ml). The filtrate was evaporated under reduced pressure. The residue
was further dried under vacuum and gave the bis p-nitrophenylacetic acid
ester.

[0073]The chemical structure was confirmed by 1H-NMR and 13C
NMR. A summary of this reaction is provided below as formula II.

##STR00003##

Example 2

[0074]A solution of the p-nitrophenylacetate (about 60 grams) produced in
Example 1 above in THF (about 300 ml) was successively treated with about
10% palladium on carbon (about 1.61 grams) and ammonium formate (about
19.1 grams). The resulting mixture was heated at about 60° C. for
about 2 hours. After cooling to room temperature, the reaction mixture
was filtered over CELITE® and the filtrate was evaporated. The
residue was partitioned between brine (about 100 ml) and ethyl acetate
(about 350 ml). The organic phase was dried over magnesium sulfate,
filtered and evaporated to give the corresponding p-aminophenyl acetic
ester. Its chemical structure was confirmed by 1H-NMR and 13C
NMR. A summary of this reaction is provided below as formula III.

##STR00004##

Example 3

[0075]A solution of the p-aminophenylacetyl ester produced in Example 2
(about 57.3 grams) in THF (about 100 ml) was slowly added using an
addition funnel to a solution of triphosgene (about 6.63 grams) in THF
(about 200 ml) at room temperature. The reaction mixture was heated at
about 65° C. overnight. The reaction mixture was evaporated and
the residue was analyzed by NMR and IR and identified as the isocyanate
prepolymer of the invention. A summary of this reaction is provided below
as formula IV.

##STR00005##

Example 4

[0076]The diisocyanate prepolymer (about 45.5 grams, about 4.41% NCO
content) prepared in Example 3 was placed in a 3-neck flask round bottom
flask and treated with trimethylolpropane (about 0.71 grams). The
resulting mixture was heated at about 65° C. for about 16 hours
and packaged into syringes. A summary of this reaction is provided below
as formula V.

##STR00006##

[0077]After sterilization by γ-irradiation, the resulting
adhesive/sealant had an isocyanate content of about 2.47%, a viscosity of
about 34905 centipoise and a lap shear of about 1238 grams.

Example 5

[0078]A solution of about 11.8 grams of p-nitrophenoxyacetic acid in about
80 ml of THF was treated with about 9.5 grams of oxalyl chloride and a
few drops of dimethylformamide. The resulting solution was stirred at
room temperature for about 1.5 hours and evaporated to dryness to give
the corresponding acid chloride. The acid chloride was combined with
about 40 grams of PEG-adipate (Mn about 1608) and the resulting
mixture was heated at about 60° C. for about 16 hours. The
reaction mixture was diluted in about 150 ml of THF and treated with
about 2 grams of activated carbon and about 10 grams of CELITE®. The
mixture was stirred for about 15 minutes, then filtered over CELITE®,
washed with about 50 ml of THF and evaporated. The residue, which was
about 40.6 grams of the p-nitrophenoxyacetate ester, was dried under
vacuum and its structure was confirmed by NMR. A summary of this reaction
is provided below as formula VI.

##STR00007##

Example 6

[0079]A solution of the p-nitrophenoxyacetate (about 40.55 grams) produced
in Example 5 above in THF (about 150 ml) was successively treated with
about 10% palladium on carbon (about 1.11 grams) and ammonium formate
(about 13.2 grams). The resulting mixture was heated at about 60°
C. for about 16 hours. After cooling to room temperature, the reaction
mixture was filtered over about 2 cm of packed alumina in a 350 ml fitted
funnel and the filtrate was evaporated. The organic phase was dried over
magnesium sulfate, filtered, and evaporated to give the corresponding
p-aminophenoxyacetate ester.

[0080]Its chemical structure was confirmed by 1H-NMR. A summary of
this reaction is provided below as formula VII.

##STR00008##

Example 7

[0081]A solution of the p-aminophenoxyacetate ester produced in Example 6
(about 25.85 grams) in THF (about 35 ml) was slowly added using an
addition funnel to a solution of triphosgene (about 2.32 grams) in THF
(about 25 ml) at room temperature. The reaction mixture was heated at
about 65° C. overnight. The reaction mixture was evaporated and
the residue was analyzed by NMR and IR and identified as the isocyanate
prepolymer of the invention. A summary of this reaction is provided below
as formula VIII.

##STR00009##

Example 8

[0082]The diisocyanate prepolymer (about 18.74 grams, about 3.66% NCO
content) prepared in Example 7 was placed in a 3-neck flask round bottom
flask and treated with trimethylolpropane (about 0.24 grams). The
resulting mixture was heated at about 65° C. for about 16 hours
and afforded the branched material. A summary of this reaction is
provided below as formula IX.

##STR00010##

Example 9

[0083]About 155.32 grams of polyethylene glycol was dried by heating at
about 105° C. and bubbling nitrogen through the material for about
4 hours. After cooling to room temperature, it was treated with about
28.9 grams of terephthaloyl chloride. The mixture was heated at about
65° C. and kept at that temperature for about 20 hours. The
reaction mixture was diluted with about 450 ml of THF, transferred into a
separatory funnel and washed with about 200 ml of brine. The two phases
were separated and the aqueous phase was extracted with about 100 ml of
THF. The combined organic phase was dried over magnesium sulfate and
alumina and filtered. The filtrate was evaporated under reduced pressure
and the residue was further dried under high vacuum to provide
polyethylene glycol terephthalate. A summary of this reaction is provided
below as formula X.

##STR00011##

Example 10

[0084]A solution of about 6.72 grams of p-nitrophenylacetic acid in about
50 ml of THF was treated with about 6.43 grams of oxalyl chloride and a
few drops of dimethylformamide. The resulting solution was stirred at
room temperature for about 1.5 hours and evaporated to dryness to give
the corresponding acid chloride. The acid chloride was combined with
about 30 grams of PEG-terephthalate (Mn about 1778) and the
resulting mixture was heated at about 60° C. for about 16 hours.
The reaction mixture was diluted with about 150 ml of THF and treated
with about 10 grams of magnesium sulfate, about 2 grams of activated
carbon and about 10 grams of CELITE®. The mixture was stirred for
about 15 minutes, then filtered over CELITE®, washed with about 50 ml
of THF and evaporated. The residue, which was the p-nitrophenylacetate
ester, was dried under vacuum and its structure was confirmed by NMR. A
summary of this reaction is provided below as formula XI.

##STR00012##

Example 11

[0085]A solution of the p-nitrophenylacetate (about 36.7 grams) produced
in Example 10 above in THF (about 150 ml) was successively treated with
about 10% Palladium on carbon (about 0.93 grams) and ammonium formate
(about 11 gram). The resulting mixture was heated overnight at about
60° C. After cooling to room temperature, the reaction mixture was
treated with magnesium sulfate (about 10 grams), CELITE® (about 5
grams) and activated carbon (about 1 gram), and stirred for about 15
minutes. It was then filtered over CELITE® and washed with about 300
ml of THF. The filtrate was evaporated and dried under high vacuum
providing the p-amino-phenylacetate. A summary of this reaction is
provided below as formula XII.

##STR00013##

Example 12

[0086]About 3.92 grams of triphosgene was placed in a 250 ml 3-neck round
bottom flask equipped with a mechanical stirrer, a condenser and an
addition funnel under static nitrogen. About 50 ml of THF was added.
After complete dissolution of triphosgene, a solution of about 36 grams
of the phenylacetylamino ester from Example 11 in about 100 ml of THF was
added dropwise. The resulting mixture was heated at about 65° C.
for about 16 hours. The THF evaporated overnight under the flow of
nitrogen, leaving the desired diisocyanate prepolymer. Its structure was
confirmed by 1H NMR and IR analyses. A summary of this reaction is
provided below as formula XIII.

##STR00014##

Example 13

[0087]About 14.98 grams of the diisocyanate prepolymer produced in Example
12 was placed in a 3-neck round bottom flask and treated with about 0.21
grams of trimethylol propane. The mixture was heated to about 65°
C. and kept at that temperature for about 20 hours to generate the
adhesive/sealant of the present disclosure. The resulting material had an
NCO content of about 1.94%, a viscosity of about 365.5 kilocentipoise and
a lap shear of about 266 grams. A summary of this reaction is provided
below as formula XIV.

##STR00015##

Example 14

[0088]About 11.98 grams of m-nitrophenoxyacetic acid was dissolved in
about 150 ml of THF and the solution was treated with about 11.22 grams
of oxalyl chloride, followed by a couple of drops of dimethyl formamide.
The resulting mixture was stirred at room temperature for about 1.5
hours, then evaporated to dryness to obtain the corresponding acid
chloride. The acid chloride was then combined with about 46 grams of
PEG-adipate. The mixture was heated at about 60° C. for about 20
hours. After cooling to room temperature, the reaction mixture was
diluted with about 300 ml of THF, treated with alumina, CELITE® and
magnesium sulfate, and stirred for about 15 minutes. It was then filtered
over CELITE® and evaporated. The residue was further dried under high
vacuum to provide about 41.7 grams of the corresponding
m-nitrophenoxyacetate ester of PEG-adipate. A summary of this reaction is
provided below as formula XV.

##STR00016##

Example 15

[0089]About 41.7 grams of m-nitrophenoxyacetate produced in Example 14 was
dissolved in about 300 ml of THF and treated with about 1.2 grams of
palladium on carbon and about 14.27 grams of ammonium formate. The
mixture was heated at about 60° C. and kept at that temperature
for about 3 hours. The mixture was treated with about 10 grams of
magnesium sulfate, about 5 grams of CELITE®, and about 1 gram of
activated carbon and stirred for about 15 minutes. It was then filtered
over CELITE® and washed with about 250 ml of THF. The filtrate was
evaporated under reduced pressure and further dried under high vacuum to
provide the desired m-aminophenoxyacetate. A summary of this reaction is
provided below as formula XVI.

##STR00017##

Example 16

[0090]About 4.97 grams of triphosgene was added to about 100 ml of THF in
a 500 ml, 3-neck round bottom flask under static nitrogen, equipped with
a mechanical stirrer, a condenser and an addition funnel. A solution of
about 39.8 grams of the m-amino-phenoxyacetate ester produced in Example
15 in about 100 ml of THF was added using the addition funnel. The
resulting mixture was heated at about 65° C. under a flow of
nitrogen for about 20 hours providing the diisocyanate prepolymer. Its
structure was confirmed by NMR and IR. A summary of this reaction is
provided below as formula XVII.

##STR00018##

Example 17

[0091]About 16.54 grams of the diisocyanate prepolymer produced in Example
16 was placed in a dry 3-neck round bottom flask and treated with about
0.21 grams of trimethylol propane. The mixture was heated to about
65° C. and kept at that temperature for about 20 hours, providing
the adhesive/sealant of the present disclosure. The resulting material
had an NCO content of about 2.92%, a viscosity of about 15 kilocentipoise
and a lap shear of about 352 grams.

[0092]A second reaction was performed under the same conditions by
reacting about 18.92 grams of the diisocyanate ester of Example 16 with
about 0.35 grams of trimethylol propane. The resulting material had an
NCO content of about 2.54%, a viscosity of about 35.4 kilocentipoise and
a lap shear of about 1020 grams. A summary of this reaction is provided
below as formula XVIII.

##STR00019##

Example 18

[0093]A solution of about 8.21 grams of p-nitrophenoxyacetic acid in about
60 ml of THF was successively treated with about 7.85 grams of oxalyl
chloride followed by a couple of drops of dimethyl formamide. The
resulting solution was stirred at room temperature for about 1.5 hours
and evaporated under reduced pressure to provide the corresponding acid
chloride. The acid chloride was then combined with about 38.9 grams of
polyethylene glycol-cyclohexyldicarboxylate
(PEG-cyclohexyldicarboxylate). The mixture was then heated at about
60° C. for about 20 hours. The reaction was diluted with about 150
ml of THF and treated with about 2 grams of activated carbon, about 10
grams of magnesium sulfate, and about 5 grams of CELITE®, and stirred
for about 15 minutes. The mixture was then filtered over CELITE® and
washed with about 50 ml of THF. The filtrate was evaporated under reduced
pressure and further dried under high vacuum to give the
p-nitrophenylacetyl ester. A summary of this reaction is provided below
as formula XIX.

##STR00020##

Example 19

[0094]A solution of about 39.2 grams of the p-nitrophenylacetyl ester
produced in Example 18 in about 200 ml of THF was successively treated
with about 0.94 grams of palladium on carbon and about 11.17 grams of
ammonium formate. The mixture was heated at about 60° C. and kept
at that temperature from about 12 to about 20 hours. The mixture was
treated with about 2 grams of activated carbon, about 10 grams of
magnesium sulfate and about 5 grams of CELITE®, and stirred for about
15 minutes. It was then filtered over CELITE® and washed with about
250 ml of THF. The filtrate was evaporated under reduced pressure, then
dried under high vacuum to provide the corresponding
p-aminophenylacetate. A summary of this reaction is provided below as
formula XX.

##STR00021##

Example 20

[0095]A solution of about 3.56 grams of triphosgene in about 250 ml of THF
was placed in a 3-neck round bottom flask under static nitrogen equipped
with a mechanical stirrer, a condenser and an addition funnel. To this, a
solution of about 34.45 grams of the p-aminophenylacetate produced in
Example 19 in about 120 ml of THF was added using the addition funnel.
The mixture was heated at about 65° C. and kept at that
temperature for a time of from about 16 to about 20 hours. The THF was
evaporated, providing the corresponding diisocyanate prepolymer. A
summary of this reaction is provided below as formula XXI.

##STR00022##

Example 21

[0096]About 13.16 grams of the diisocyanate prepolymer produced in Example
20 was placed in a dry 3-neck round bottom flask and treated with about
0.09 grams of trimethylol propane. The mixture was heated at about
65° C. and kept at that temperature for about 20 hours, providing
an adhesive/sealant of the present disclosure. The resulting material had
an NCO content of about 2.73%, a viscosity of about 20.6 kilocentipoise
and a lap shear of about 0 grams. A summary of this reaction is provided
below in formula XXII.

##STR00023##

[0097]It will be understood that various modifications may be made to the
embodiments disclosed herein. For example, the compositions in accordance
with this disclosure can be blended with other biocompatible,
bioabsorbable or non-bioabsorbable materials. As another example,
optional ingredients such as dyes, fillers, medicaments or antimicrobial
compounds can be added to the composition. Therefore, the above
description should not be construed as limiting, but merely as
exemplifications of embodiments. Those skilled in the art will envision
other modifications within the scope and spirit of the claims appended
hereto.